ABSTRACT: There are about 600,000 patients with refractory epilepsy in the United States. Since those patients? seizures cannot be controlled by any drugs, epilepsy surgery is the only potential cure. To be successful, epilepsy surgery requires a preoperative evaluation to define the epileptogenic zone, which is the brain area that should be resected to achieve seizure freedom. One widely used method for estimating the epileptogenic zone is to place electrodes on the brain surface to capture spikes (typically, 14-70 Hz). The brain areas generating ictal spikes are conventionally assumed to be the ?epileptogenic zones?. Approximately 44% of patients may have seizures within 30 days after undergoing the conventional surgery. To improve the efficacy of surgical treatment, there is an overriding need for reliable biomarkers that can localize the true epileptogenic zones. Recent studies have found that the removal of brain areas generating high frequency oscillations (HFOs), which include ripples (80-250 Hz) and fast ripples (250-600 Hz), can result in favorable clinical outcomes. The localization of HFOs typically requires invasive intracranial recordings that are costly and are associated with morbidity and potential mortality. The present proposal aims to develop a non-invasive method to localize HFOs by using magnetoencephalography (MEG). According to emerging data, MEG is particularly advantageous compared to other potential technologies such as scalp electroencephalography because MEG is less affected by skull conductivity and is less susceptible to contamination from muscular activity. Our central hypothesis is that MEG HFOs will enable clinicians to localize the true epileptogenic zones noninvasively, which will result in good surgical outcomes for patients. To test the hypothesis, we propose the following two studies. The first study is to measure the spatial concordance between HFOs localized by MEG and by electrocorticography (ECoG). The working hypothesis is that epileptogenic zones determined by invasive ECoG can be non-invasively localized by MEG HFOs. This study will quantify the distance between the source locations of MEG HFOs and the location of ECoG HFOs. The second study is to assess surgical outcomes after resection of brain areas generating traditional ictal spikes and HFOs. The working hypothesis is HFOs are reliable biomarkers for epileptogenic foci and can significantly change the outcomes of epilepsy surgery. We plan to quantify the relationships between clinical outcomes and the resections of brain areas generating spikes, ripples and fast ripples. If neurosurgeons were able to accurately pinpoint the true epileptogenic zones before surgery, patients with intractable epilepsy would have much higher chance of seizure freedom. Those patients, whose epileptogenic zones cannot be localized pre-surgically, may be able to benefit from surgery by using MEG HFO based pre-surgical evaluation. It is anticipated that MEG HFOs, which can be non-invasively and repetitively measured, will be new biomarkers for clinicians and scientists to develop novel therapeutic strategies for a variety of types of epilepsy in the future.